Atrial mitochondrial calcium handling in patients with atrial fibrillation

by Julius Ryan Pronto
Doctoral thesis
Date of Examination:2023-01-25
Date of issue:2023-05-30
Advisor:Prof. Dr. Niels Voigt
Referee:Prof. Dr. Niels Voigt
Referee:Prof. Dr. Peter Rehling
Persistent Address: http://dx.doi.org/10.53846/goediss-9901

 

 

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Abstract

English

Atrial fibrillation (AF) is the most common form of arrhythmia however, due to the incomplete understanding of its molecular mechanisms, there are several limitations of the currently available therapeutic strategies. Impaired cytosolic calcium (Ca2+) handling is a well-described mechanism in the persistent form of AF. Mitochondria comprise up to a third of the volume of cardiac myocytes and are able to take up Ca2+ from the cytosol. One function of mitochondrial Ca2+ accumulation is to increase cellular energy production, matching bioenergetic supply with demand. A disturbance in this process in the ventricle has already been observed in cardiovascular diseases. Mitochondrial Ca2+ handling, however, is not well-studied in the atria and in AF. Here, we show a disturbance in the interaction between the sarcoplasmic reticulum and mitochondria in the right atrial appendage from patients with long-standing persistent atrial fibrillation (AF). The close apposition of these “kissing cousins” generates Ca2+ microdomains which facilitate efficient Ca2+ uptake by mitochondria. This appears to be altered in AF, as Mitochondrial Ca2+ transient amplitude and diastolic Ca2+ accumulation are reduced, compared to non-AF myocytes, particularly in conditions of increased workload. As a consequence, Ca2+-activated mitochondrial processes are impaired, such as the regeneration of electron donors necessary for ATP production and, potentially also, mitochondrial mechanisms protecting against cellular oxidation. We have, however, found a possible compensatory mechanism involving the mitochondria Ca2+ uniporter (MCU) complex, whereby a decrease in MICU2/MCU ratio could prevent detrimental Mitochondrial Ca2+ loss. We also provide new evidence in human atrial myocytes and human induced-pluripotent stem cell derived cardiac myocytes (hiPSC-CMs) for the antiarrhythmic potential of ezetimibe, a lipid-lowering drug, recently shown to enhance Mitochondrial Ca2+ uptake. Overall, the findings of this project highlight the significance of altered Mitochondrial Ca2+ handling, particularly in the face of increased bioenergetic demands, in AF. Furthermore, evidence is shown that enhancing mitochondrial Ca2+ uptake can protect against potentially arrhythmogenic mechanisms underlying AF.
Keywords: mitochondria; calcium; atrial fibrillation